Effects of Exercise Alone or Combined With Cognitive Training and Vitamin D Supplementation to Improve Cognition in Adults With Mild Cognitive Impairment

Key Points Question Does a multidomain intervention of aerobic-resistance exercises with cognitive training and vitamin D improve cognition in older adults with mild cognitive impairment? Findings In this randomized clinical trial including 175 Canadian adults aged 65 to 84 years, a 20-week multidomain intervention of aerobic-resistance exercises with computerized cognitive training had a larger effect in improving cognition than exercise interventions alone, and these improvements were maintained at 12-month follow-up. Vitamin D addition did not enhance the effect. Meaning These findings suggest that pairing aerobic and resistance exercises with sequential computerized cognitive training may improve cognition in older adults with mild cognitive impairment.


Introduction
Over 50 million worldwide lived with dementia in 2021, with associated costs exceeding $800 billion US. 1 There is no cure for dementia, but there has been a fundamental shift to target those at risk using nonpharmacological and lifestyle interventions to improve cognition and potentially delay dementia onset. 2,3 Mild cognitive impairment (MCI) is an intermediate state between normal cognitive aging and early dementia, the optimal period to intervene with preventive strategies and early treatments. 4 Both aerobic exercise and resistance training have been demonstrated to improve cognition in older adults, although the benefits of combining these 2 modalities are unclear. 5 Computer-based cognitive training also improves cognition in older adults through the repeated engagement of cognitive processes using challenging and preferably adaptive tasks. 6 Furthermore, vitamin D in addition to exercise and cognitive training has been argued to enhance cognition due to its neuroprotective attributes. 7 Thus, providing these interventions together, as a multidomain treatment, has the potential to delay progression from MCI to dementia. 8,9 Previous multidomain intervention trials in healthy older adults have demonstrated primary efficacy in improving cognition, as in the FINGER (Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability) trial, 10 and post hoc analyses of specific higher-risk subgroups in the MAPT (Multidomain Alzheimer Preventive Trial) 11 and PREDIVA (Prevention of Dementia by Intensive Vascular Care) trials. 12 However, the effect of multidomain interventions in cognitively impaired populations remains elusive. The recent MEDEX (Mindfulness-Based Stress Reduction, Health Education and Exercise) factorial trial failed to show an effect of combining mindfulness training and exercise to improve cognition in older adults with subjective cognitive concerns. 13 In MCI populations, multidomain trials coupling exercise with other interventions have shown mixed results. 14 In particular, 2 previous randomized factorial trials demonstrated that combining exercise with cognitive training was less effective than exercises alone in improving cognition. 15,16 Similarly, the sustainability of any cognitive improvements following interventions have not yet been established. The SYNERGIC Trial 17 (Synchronizing Exercises, Remedies in Gait and Cognition) was conducted to evaluate the cognitive benefits of an aerobic-resistance exercise regime, alone or in addition to computer-based cognitive training, and vitamin D supplementation in older adults with MCI.

Study Design
The SYNERGIC Trial was a double-masked, randomized trial with a fractional factorial design to All participants provided written informed consent. SYNERGIC adhered to the Consolidated Standards of Reporting Trials Extension (CONSORT Extension) reporting guidelines, as extended to nonpharmacologic interventions. 18 Participants Participants were aged 60 to 85 years, recruited from the community, who fulfilled MCI criteria 19 : (1) subjective cognitive concerns; (2) objective cognitive impairment in memory, executive function, attention, and/or language; (3) preserved activities of daily living; and (4) absence of dementia (eMethods in Supplement 2). Exclusion included major depression, schizophrenia, substance abuse, parkinsonism, conditions affecting gait (eg, severe osteoarthritis, previous stroke), exercise program participation, and taking vitamin D doses greater than 1000 IU per day, cognitive enhancers, or anticholinergics. Ethnicity of participants was assessed using the CCNA ethnicity questionnaire, to characterize minority representation in our study. Full eligibility criteria are detailed in our protocol 17 (Supplement 1).

Randomization and Masking
Participants were randomly assigned into arms in a 1:1:1:1:1 ratio using a central computer-generated random number sequence in blocks of 5: arm 1 (aerobic-resistance exercise, cognitive training, and vitamin D); arm 2 (exercise, cognitive training, and placebo vitamin D); arm 3 (exercise, sham cognitive training, and vitamin D); arm 4 (exercise, sham cognitive training, and placebo vitamin D); and arm 5 (balance and toning exercise, sham cognitive training, and placebo vitamin D). A research pharmacist assigned vitamin D or placebo capsules as kits in compliance with the randomization list(s).
Arm allocation was not disclosed to participants, who were asked not to discuss the intervention during training sessions. Outcome assessors were masked to allocation and not involved in the interventions.

Procedures
Participants in all 5 study arms completed group-training sessions 3 times per week for 20 weeks.
Each session lasted 90 minutes and included 30 minutes of cognitive training (active or sham), followed by 60 minutes of aerobic-resistance or the control exercise (balance and toning). All participants received a capsule of vitamin D (a 10 000 IU dose) or matching placebo 3 times per week for 20 weeks.
Participants performed cognitive training (Neuropeak; detailed description in eMethods in Supplement 2) or sham cognitive training on a computerized tablet (Apple). Neuropeak delivered 2 visuomotor tasks targeting working memory and attention separately and concurrently. Level of difficulty increased over time, and participants received individually tailored continuous feedback on performance. 20 Sham cognitive training included alternating between 2 tasks (touristic search and video watching) with the same time exposure as the intervention training.
The supervised progressive exercise program combined aerobic and resistance training based on exercise prescription for older adults (eMethods in Supplement 2). 21 Exercise progress and intensity were monitored using the Borg Rating of Perceived Exertion. 22 Control exercises included stretching, balance, and toning exercises that did not progress in volume or intensity. Exercise groups had approximately a trainer-to-participants ratio of 1:4. To maximize intervention fidelity, all trainers followed the same manual of procedures and met biweekly to review progress. Participants attended at least 85% of sessions and were followed up by telephone if absent.
is considered more sensitive to executive function by incorporating 5 additional tests (eMethods in Supplement 2). Scores range from 0 to 85, with higher scores indicating worse cognition. ADAS-Cog-13 is recommended as a robust primary outcome in MCI trials for its responsiveness. 23 However, the rationale for including the Plus variant relates to previous studies demonstrating that exercise may exert greater effects on executive function than other cognitive domains. 24 Significant improvements in either ADAS-Cog-13 or the Plus variant at month 6 was considered proof of efficacy. 25,26 Individual ADAS-Cog-13 and Plus items were analyzed as secondary cognitive outcomes (statistical analysis plan in Supplement 1).

Sample Size Calculation
Assuming the primary outcome data follow approximately a normal distribution, a trial with 1:4 ratio (control:exercise arms) would require 170 participants to detect an effect size of 0.54 with 80% power at a 2-sided, 5% significance level. This sample size was inflated to 200 (40 per arm) to account for potential attrition of 15%.

Statistical Analysis
Following the intention-to-treat principle, all randomized individuals were included in the primary analysis (Figure 1; statistical analysis plan available in Supplement 1). Outcomes were analyzed using a linear mixed model approach with repeated measures. 27 Models were fitted with participantspecific random intercept and fixed effects of time, intervention arm, and time-by-intervention-arm interaction, and adjusted for age, sex, education, and comorbidities.
Between-arms comparisons followed our protocol and statistical analysis plan, which aligns with the recommended analysis and reporting of factorial trials. 28,29 For comparisons, what have been described as "inside the table" analyses were employed to compare each intervention arm with the control arm (arm 5), while "at the margin" analyses were conducted by pooling arms in prespecified combinations to examine potential synergism. Participants that received both exercise and cognitive intervention (arms 1 and 2) and participants that received exercise but sham cognitive intervention (arms 3 and 4) were compared with the control (arm 5). To facilitate the interpretation of treatment effects on primary and secondary outcomes, we calculated effect sizes, defined as differences divided by standard deviation, 30 and the proportion of participants with a clinically significant improvement in primary outcomes.
The durability of the intervention effect from baseline and postintervention to follow-up (month 12) was assessed for primary and secondary outcomes using linear mixed models with all 3 time points.
Adjustments for multi-arm comparisons were not made as the trial is intended to compare the intervention effect with the control rather than pairwise, and no adjustments for having 2 primary outcomes were executed. 31 Interpretation of statistical tests were based on a 2-sided 5% significance level. All analyses were conducted in SPSS version 23.0 (SPSS Inc) and R version 3.

Primary Outcome
In alignment with our design, a planned marginal analysis to test different orders of interactions was employed. Compared with control (arm 5) and regardless of the addition of cognitive training or vitamin D, ADAS-Cog-13 scores improved significantly in participants that received the exercise regime (arms 1 through 4: mean difference, 1.79 points; 95% CI, −3.27 to −0.31 points; P = .02; Table 2). Compared with the participants that received only the exercise regime (arms 3 and 4), those who received both exercise regime and cognitive training (arms 1 and 2) had significant    (Figure 2). The difference between the exercise regime (arms 3 and 4) and the control (arm 5) on ADAS-Cog-13 was not statistically significant ( Table 3)      Adding vitamin D intervention b Between-group differences were assessed using the interaction between time × intervention arm. Lower scores indicate cognitive improvement.

Secondary Outcomes
The interventions effect on individual ADAS-Cog items are shown in Tables 2 and 3. A significant   improvement was observed for delayed recall (mean difference: arm 2

Adherence and Adverse Events
There were no group differences in the median training duration. Adherence to exercise regimes, cognitive training, and their respective control conditions, were equivalent across the 5 arms (87%).

Discussion
The primary objective of the SYNERGIC Trial was to evaluate the effect of a multidomain intervention (combination of progressive exercise with cognitive training and vitamin D supplementation) on    improvements observed in the ADAS-Cog-13 immediately after the intervention were slightly attenuated at 12-month assessment but they did not revert to baseline scores, suggesting a lasting effect even without participants engaging in exercise regimes during the follow-up period. Finally, our multidomain intervention achieved high compliance and adherence, and was safe and feasible to perform in older adults with MCI.
A 2.64-point improvement in the ADAS-Cog-13 for the multidomain intervention is larger than changes seen in previous pharmaceutical trials among individuals with MCI or mild dementia, 32 and approaches the 3 points considered clinically meaningful. 33 Together with the moderate-to-large effect size (0.71) found, our results support a beneficial cognitive effect from this multidomain intervention.
The lack of significant effect on the ADAS-Cog-Plus was against our hypotheses. Changes for arms 1 and 2 (exercise plus cognitive training) were in the expected direction, which prompted us to conduct exploratory analyses to evaluate whether adding items to the ADAS-Cog-13 may have reduced its responsiveness to our interventions. These post hoc analyses revealed that the ADAS-Cog-Plus variant without the verbal category fluency item (just adding 4 out of 5 plus items to the ADAS-Cog-13) was sensitive in detecting significant improvements for our multidomain intervention.
Adding items to a composite measure would increase its sensitivity only to the extent that it may improve the mean-to-SD ratio of change over the course of the study. In other words, the optimal composite maximizes the signal and minimizes the noise. Adding the category fluency may have reduced the responsiveness of the Plus variant to our intervention because exercise and dual-task cognitive training interventions typically show greatest effects on measures of attention and pure executive function rather than on verbal fluency. 24,35 Our results align with a 2022 meta-analysis 14 showing a significant effect of multidomain interventions in MCI for improving global cognition, executive function, and episodic memory.
Interestingly, only 7 of the 28 trials included in the meta-analysis combined aerobic-resistance exercise with cognitive training and none of them showed that the multidomain intervention has a larger effect than exercise alone. Our trial is to our knowledge the first to show a greater effect of a multidomain intervention over exercise alone. The lack of cognitive improvements in previous MCI multidomain interventional trials could be related to the substantial heterogeneity among intervention protocols, as well as a lack of meaningful exercise progression.
The lack of improvement with vitamin D may be related to normal-high serum values (greater than 70 nmol/L) in our participants at enrollment, whereas benefits of vitamin D supplementation may only occur in the presence of severe 25-hydroxyvitamin D deficiency (below 30 nmol/L). 35 We could not perform a subanalysis by deficiency status as only 4 participants were severely deficient, but this should be a target for future research since vitamin D deficiency is associated with impaired executive function and progression to dementia. 34 Exercise training cessation may induce detraining effects, 36 but maintenance of cognitive improvements was reported in short follow-ups. 37 In this trial, ADAS-Cog-13 improvements diminished slightly at 12-month follow-up but did not revert to baseline levels for arms 1, 2, and 3.
Such findings suggest potential maintenance of the cognitive improvements up to 6-month postintervention for exercise with cognitive training or vitamin D.

Strengths and Limitations
Strengths of our trial included the selection of a fractional factorial design to test the sparsity-ofeffects principle and, therefore, expose interaction effects over low-order interactions, such as the